US2015072942A1PendingUtilityA1
Boronic ester and acid compounds, synthesis and uses
Est. expiryOct 28, 2014(expired)· nominal 20-yr term from priority
A61P 9/00A61P 37/06A61P 43/00A61P 37/00A61P 35/00A61P 29/00A61P 31/00A61P 31/04A61P 31/18A61P 19/02A61P 17/00A61P 17/06A61P 19/10A61P 19/00A61P 11/06A61K 38/00C07K 5/06191C07K 5/06043C07K 5/0827C07F 5/025C07F 5/04C07K 5/06C07K 5/0808C07K 5/06139C07C 229/26A61K 31/185C07D 295/14A61K 31/535
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Claims
Abstract
Disclosed herein is a method for reducing the rate of degradation of proteins in an animal, comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed herein are novel boronic ester and acid compounds, their synthesis and uses.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
wherein
P is R 7 —C(O)— or R 7 —SO 2 —, where R 7 is one of aryl, aralkyl, heteroaryl or heteroarylalkyl, the ring portion of any of which can be optionally substituted, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl;
B 1 at each occurrence, is independently one of N or CH;
X 1 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 1 is N, then the X 1 attached to said B 1 is —C(O)—NH—;
X 2 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R is hydrogen or alkyl, or R forms together with the adjacent R 1 , or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 1 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A is 0, 1 or 2.
2 . The compound of claim 1 , wherein:
A is zero; X is —C(O)—NH—; R is hydrogen or C 1-8 alkyl; and R 3 is C 1-6 alkyl.
3 . The compound of claim 2 , wherein R 3 is C 4 alkyl.
4 . The compound of claim 1 , wherein:
P is R 7 —C(O)— or R 7 —SO 2 —, where R 7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl or pyrrolyl, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl.
5 . The compound of claim 1 , wherein P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl.
6 . The compound of claim 5 , wherein P is one of 8-quinolinecarbonyl, 8-quinolinesulfonyl, 2-quinoxalinecarbonyl, 2-quinoxalinesulfonyl, 2-pyrazinecarbonyl, 2-pyrazinesulfonyl, 3-furancarbonyl, 3-furansulfonyl or N-morpholinecarbonyl.
7 . The compound of claim 1 , wherein A is 0.
8 . The compound of claim 1 , wherein B 1 , at each occurrence, is CH.
9 . The compound of claim 8 , wherein X 1 , at each occurrence, is —C(O)—NH—.
10 . The compound of claim 9 , wherein X 2 is —C(O)—NH—.
11 . The compound of claim 1 , wherein R is hydrogen or C 1-8 alkyl.
12 . The compound of claim 1 , wherein:
R 1 , at each occurrence, and R 2 and R 3 are each independently one of hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, a 5-, 6-, 9- or 10-membered heteroaryl group, or —CH 2 —R 5 ; R 5 , in each instance, is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, C 3-10 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio or a 5-, 6-, 9- or 10-membered heteroaryl group; where the ring portion of any of said aryl, aralkyl, alkaryl or 5-, 6-, 9- or 10-membered heteroaryl groups of R 1 , R 2 , R 3 and R 5 can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylthio, C 6-10 arylsulfinyl, C 6-10 arylsulfonyl, C 6-10 aryl, C 1-6 alkyl(C 6-10 )aryl, and halo(C 6-10 )aryl.
13 . The compound of claim 1 , wherein R 3 is C 1-12 alkyl.
14 . The compound of claim 1 , wherein R 3 is C 1-6 alkyl.
15 . The compound of claim 1 , wherein R 3 is C 4 alkyl.
16 . The compound of claim 1 , wherein R 3 is isobutyl.
17 . The compound of claim 1 , wherein R 2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-pyridylmethyl, 2-pyridylmethyl 6-quinolinylmethyl, 3-indolylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(2′-pyridylmethoxy)benzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl.
18 . The compound of claim 1 , wherein Z 1 and Z 2 are independently one of C 1-6 alkyl, hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy.
19 . The compound of claim 18 , wherein Z 1 and Z 2 are both hydroxy.
20 . The compound of claim 1 , wherein together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
21 . The compound of claim 1 , wherein:
P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl; A is zero; X 2 is —C(O)—NH—; R is hydrogen or C 1-8 alkyl; R 2 and R 3 are each independently one of hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, pyridylmethyl, or quinolinylmethyl; and Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
22 . The compound of claim 1 , wherein:
P is one of 8-quinolinecarbonyl, 8-quinolinesulfonyl, 2-quinoxalinecarbonyl, 2-quinoxalinesulfonyl, 2-pyrazinecarbonyl, 2-pyrazinesulfonyl, 3-pyridinecarbonyl, 3-pyridinesulfonyl, 3-furancarbonyl, 3-furansulfonyl or N-morpholinecarbonyl; A is zero; X 2 is —C(O)—NH—; R is hydrogen or C 1-8 alkyl; R 3 is isobutyl; R 2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-pyridylmethyl, 2-pyridylmethyl 6-quinolinylmethyl, 3-indolylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(2′-pyridylmethoxy)benzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl; and Z 1 and Z 2 are independently one of hydroxy, C 1-6 alkoxy, C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
23 . The compound of claim 1 , wherein said compound is one of:
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid, N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
24 . The compound of claim 23 , wherein said compound is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, or an isostere, pharmaceutically acceptable salt or boronate ester thereof.
25 . A compound having the formula:
wherein
P is hydrogen or an amino-group-protecting moiety;
B 1 , at each occurrence, is independently one of N or CH;
X 1 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 1 is N, then the X 1 attached to said B 1 is —C(O)—NH—;
X 2 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R is hydrogen or alkyl, or R forms together with the adjacent R 1 , or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, aryl, alkoxy or aryloxy;
R 1 at each occurrence, R 2 and R 3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
provided that at least one R 1 , R 2 or R 3 is naphthylmethyl, pyridylmethyl or quinolinylmethyl;
Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A is 0, 1, or 2;
provided that the compound is other than isovaleryl-phenylalanine-norvaline-[(naphthylmethyl), (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)]methylamide or (3-t-butylsulfonyl)propionyl-norvaline-(1-naphthyl, dihydroxyboryl)methylamide.
26 . The compound of claim 25 , wherein P is R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —O—C(O)—, and
R 7 is one of alkyl, aryl, alkaryl, aralkyl, heteroaryl or heteroarylalkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, then R 7 can also be saturated or partially saturated heterocycle.
27 . The compound of claim 25 , wherein P is R 7 —C(O)— or R 7 —SO 2 —; and
R 7 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl(C 1-6 )alkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl.
28 . The compound of claim 25 , wherein B 1 is CH, and X 1 and X 2 are each —C(O)—NH—.
29 . The compound of claim 25 , wherein R 1 and R 2 are independently selected from the group consisting of alkyl and —CH 2 —R 5 , where R 5 is one of C 6-10 aryl, C 1-10 alk(C 6-10 )aryl, C 3-10 cycloalkyl, or a 5-, 6-, 9- or 10-membered heterocycle.
30 . The compound of claim 25 , wherein A is zero.
31 . The compound of claim 25 , wherein R 2 is quinolinylmethyl.
32 . The compound of claim 25 , wherein said compound is one of:
N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, or N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid; or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
33 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
wherein
P is hydrogen or an amino-group-protecting moiety;
B 1 , at each occurrence, is independently one of N or CH;
X 1 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 1 is N, then the X 1 attached to said B 1 is —C(O)—NH—;
X 2 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R forms together with the adjacent R 1 , or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy and aryloxy;
when A is 2, the R 1 that is not adjacent to N—R is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 ;
when A is 1 or 2, R 2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 ;
R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 ;
R 5 , in each instance, is independently one of aryl, aralkyl, alkaryl, cycloalkyl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl;
Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A is 0, 1, or 2.
34 . The compound of claim 33 , wherein the nitrogen-containing ring system is selected from the group consisting of:
35 . The compound of claim 33 , wherein P is R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —O—C(O)—, and
R 7 is one of alkyl, aryl, alkaryl, aralkyl, heteroaryl or heteroarylalkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, then R 7 can also be saturated or partially saturated heterocycle.
36 . The compound of claim 35 , wherein P is R 7 —C(O)— or R 7 —SO 2 —; and
R 7 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl(C 1-6 )alkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl.
37 . The compound of claim 33 , wherein B 1 is CH, and X 1 and X 2 are each —C(O)—NH—.
38 . The compound of claim 33 , wherein R 1 and R 2 are independently selected from the group consisting of alkyl and —CH 2 —R 5 , where
R 5 , in each instance, is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, C 3-10 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio or a 5-, 6-, 9- or 10-membered heteroaryl group, where the ring portion of any of said C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, or 5-, 6-, 9- or 10-membered heteroaryl can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylthio, C 6-10 arylsulfinyl, C 6-10 arylsulfonyl, C 6-10 aryl, C 1-6 alkyl(C 6-10 )aryl and halo(C 6-10 )aryl.
39 . The compound of claim 33 , wherein A is zero.
40 . The compound of claim 33 , wherein P is hydrogen.
41 . The compound of claim 33 , wherein:
A is zero; P is hydrogen; X 2 is —C(O)—NH—; R forms together with the adjacent R 2 , a nitrogen-containing ring system selected from the group consisting of:
R 3 is C 1-6 alkyl; and
Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
42 . The compound of claim 33 , wherein said compound is L-proline-L-leucine boronic acid, or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
43 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
wherein
P is hydrogen or an amino-group-protecting moiety;
B 1 , at each occurrence, is independently one of N or CH;
X 1 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 1 is N, then the X 1 attached to said B 1 is —C(O)—NH—;
X 2 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R is hydrogen or alkyl, or R forms together with the adjacent R 1 , or when A is zero, forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy;
R 1 at each occurrence, R 2 and R 3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
provided that at least one R 1 , R 2 or R 3 is
where R 9 is one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl; wherein the alkyl is optionally substituted with one of C 1-6 alkyl, halogen monohalo (C 1-6 ) alkyl, and trifluoromethyl; and wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups can be optionally substituted with one or two of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylthio, C 6-10 arylsulfinyl, C 6-10 arylsulfonyl, C 6-10 aryl, C 1-6 alkyl(C 6-10 )aryl, and halo(C 6-10 )aryl;
A 1 and A 2 are independently one of hydrogen, halogen, C 1-6 alkyl, monohalo(C 1-6 )alkyl, or trifluoromethyl;
Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A is 0, 1, or 2.
44 . The compound of claim 43 , wherein P is R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —O—C(O)—, and
R 7 is one of alkyl, aryl, alkaryl, aralkyl, heteroaryl or heteroarylalkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, then R 7 can also be saturated or partially saturated heterocycle.
45 . The compound of claim 43 , wherein P is R 7 —C(O)— or R 7 —SO 2 —; and
R 7 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl(C 1-6 )alkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl.
46 . The compound of claim 43 , wherein X 1 and X 2 are each —C(O)—NH—.
47 . The compound of claim 43 , wherein one of R 1 , R 2 or R 3 is
where
A 1 and A 2 are independently one of hydrogen, C 1-6 alkyl, halogen, monohalo (C 1-6 ) alkyl or trifluoromethyl;
R 9 is one of C 1-8 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, a 5-to 10-membered heteroaryl or a 5- to 10-membered heteroaryl(C 1-6 )alkyl;
and the remaining R 1 , R 2 and R 3 are independently selected from the group consisting of alkyl and —CH 2 —R 5 , where
R 5 , in each instance, is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, C 3-10 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio or a 5-, 6-, 9- or 10-membered heteroaryl group, where the ring portion of any of said C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, C 1-6 alk(C 6-10 )aryl, or 5-, 6-, 9- or 10-membered heteroaryl can be optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl(C 3-8 )cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, cyano, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C 1-6 )alkoxy, trifluoromethyl, halogen, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryl(C 1-6 )alkyl, C 6-10 aryl(C 1-6 )alkoxy, hydroxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 6-10 arylthio, C 6-10 arylsulfinyl, C 6-10 arylsulfonyl, C 6-10 aryl, C 1-6 alkyl(C 6-10 )aryl and halo(C 6-10 )aryl.
48 . The compound of claim 43 , wherein A is zero.
49 . The compound of claim 43 , wherein:
A is zero; P is one of R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —C(O)—; R 7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl or pyrrolyl, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl; X 2 is —C(O)—NH—; R 2 is:
where
A 1 and A 2 are independently one of hydrogen, C 1-6 alkyl, halogen, monohalo (C 1-6 ) alkyl or trifluoromethyl;
R 9 is one of hydrogen, C 1-8 alkyl, phenyl, benzyl, phenethyl or pyridylmethyl;
R 3 is C 1-6 alkyl; and
Z 1 and Z 2 are both hydroxy, C 1-6 alkoxy, or C 6-10 aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.
50 . The compound of claim 43 , wherein said compound is one of:
N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, or N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
51 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
wherein
A is zero;
P is hydrogen or an amino-group-protecting moiety;
X 2 is one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R is hydrogen or alkyl, or R forms together with the adjacent R 2 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, where said ring system can be optionally substituted by one or two of keto, hydroxy, aryl, alkoxy or aryloxy;
R 2 and R 3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; and
Z 1 and Z 2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z 1 and Z 2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O;
provided that P is not C 1-6 alkoxycarbonyl, C 1-4 alkylcarbonyl or phenyl(C 1-3 )alkyl.
52 . The compound of claim 51 , wherein P is R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —O—C(O)—, and
R 7 is one of alkyl, aryl, alkaryl, aralkyl, heteroaryl or heteroarylalkyl, where the ring portion of any of said aryl, alkaryl, aralkyl, heteroaryl or heteroarylalkyl can be optionally substituted, or when P is R 7 —C(O)—, then R 7 can also be a saturated or partially unsaturated heterocycle.
53 . The compound of claim 51 , wherein P is R 7 —C(O)— or R 7 —SO 2 —; and
R 7 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, a 5- to 10-membered heteroaryl or a 5- to 10-membered heteroaryl(C 1-6 )alkyl, any of which can be optionally substituted, or when P is R 7 —C(O)—, R 7 can also be N-morpholinyl.
54 . The compound of claim 51 , wherein B 1 is CH, and X 1 and X 2 are each —C(O)—NH—.
55 . The compound of claim 51 , wherein R 2 and R 3 are independently selected from the group consisting of C 1-8 alkyl and —CH 2 —R 5 , where R 5 is one of C 6-10 aryl, C 1-6 alk(C 6-10 )aryl, C 6-10 ar(C 1-6 )alkyl, C 3-8 cycloalkyl, or a 5-, 6-, 9- or 10-membered heterocycle.
56 . The compound of claim 51 , which is N-(3-phenylpropionyl)-L-phenylalanine-L-leucine boronic acid, or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
57 . The compound of claim 51 , wherein said compound is one of:
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid, N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, or N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or isosteres, pharmaceutically acceptable salts or boronate esters thereof.
58 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
wherein
Y is one of R 8 —C(O)—, R 8 —SO 2 —, R 8 —NH—C(O)— or R 8 —O—C(O)—, where R 8 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 8 —C(O)— or R 8 —SO 2 —, then R 8 can also be an optionally substituted 5-10 membered, saturated, partially unsaturated or aromatic heterocycle;
X 3 is a covalent bond or —C(O)—CH 2 —;
R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; and
Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form a moiety derived from dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O;
provided that when Y is R 8 —C(O)—, R 8 is other than phenyl, benzyl or C 1-3 alkyl.
59 . The compound of claim 58 , wherein P is R 8 —C(O)— or R 8 —SO 2 —; and
R 8 is one of C 6-10 aryl, C 6-10 ar(C 1-6 )alkyl, or a 5-10 membered heteroaryl, any of which can be optionally substituted, or when P is R 8 —C(O)—, R 8 can also be N-morpholinyl.
60 . The compound according to claim 58 , wherein Y is one of
where R 4 is C 6-12 alkyl.
61 . A compound having the formula:
and pharmaceutically acceptable salts thereof;
where
Y is
P is one of R 7 —C(O)—, R 7 —SO 2 —, R 7 —NH—C(O)— or R 7 —O—C(O)—, where R 7 is one of alkyl, aryl, alkaryl, aralkyl, any of which can be optionally substituted, or when Y is R 7 —C(O)— or R 7 —SO 2 —, R 7 can also be an optionally substituted 5-10 membered saturated, partially unsaturated or aromatic heterocycle;
X 3 is a covalent bond or —C(O)—CH 2 —;
R 1 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 5 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 5 , in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R 6 , where W is a chalcogen and R 6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; and
Z 1 and Z 2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form a moiety derived from dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O.
62 . The compound of claim 61 , wherein Y is:
63 . A pharmaceutical composition, comprising a compound of claims 1 , 25 , 33 , 43 , 51 , 58 or 61 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
64 . A pharmaceutical composition, comprising a compound of claims 22 , 28 , 41 , 49 , 55 , 60 and 62 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
65 . A pharmaceutical composition, comprising a compound of claims 23 , 32 , 42 , 50 , 56 and 57 or an isostere, pharmaceutically acceptable salt or boronate ester thereof, and a pharmaceutically acceptable carrier or diluent.
66 . The pharmaceutical composition of claim 65 , wherein said compound is present in an amount effective to inhibit the proteasome function in a mammal.
67 . A method of inhibiting the growth of a cancer cell, comprising contacting a cell in need of such inhibiting with an effective growth-inhibiting amount of a compound of claims 1 , 25 , 33 , 43 , 51 , 58 or 61 .
68 . A method for reducing the rate of muscle protein degradation in a cell comprising contacting a cell in need of said reducing with an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2
69 . A method for reducing the activity of NF-κB in a cell, comprising contacting a cell in need of said reducing with an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
70 . A method for reducing the rate of intracellular protein breakdown, comprising contacting cells in need of said reducing with an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
71 . A method for reducing the rate of degradation of p53 protein in a cell, comprising administering to a cell in need of said reducing an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH—NH 2 —, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
72 . A method for inhibiting cyclin degradation in a cell, comprising contacting a cell in need of said reducing with an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
73 . A method of preventing or treating an inflammatory condition in a patient in need thereof, said method comprising administering to said patient a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
74 . The method of claim 73 , wherein said patient has been diagnosed with, or is at risk of developing, a condition selected from the group consisting of tissue rejection, organ rejection, arthritis, an infection, dermatoses, inflammatory bowel disease, and an autoimmune disease.
75 . A method for inhibiting antigen presentation in a cell comprising administering to a cell in need thereof an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
76 . A method for inhibiting inducible NF-κB dependent cell adhesion in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof;
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH 2 —NH—, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy;
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
77 . A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor of the formula:
or a pharmaceutically acceptable salt thereof:
wherein
P 10 is hydrogen or an amino-group-protecting moiety;
B 11 is independently one of N or CH;
X 11 , at each occurrence, is independently one of —C(O)—NH—, —CH 2 —NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —CH(OH)—CH—NH 2 —, —CH═CH—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—, provided that when B 11 is N, then X 11 is —C(O)—NH;
X 12 is one of —C(O)—NH—, —CH(OH)—CH 2 —, —CH(OH)—CH(OH)—, —C(O)—CH 2 —, —SO 2 —NH—, —SO 2 —CH 2 — or —CH(OH)—CH 2 —C(O)—NH—;
R 10 is hydrogen or alkyl, or R 10 forms together with the adjacent R 11 , or when A 10 is zero, forms together with the adjacent R 12 , a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy:
R 11 , at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
R 12 and R 13 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH 2 —R 15 , where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted,
where R 15 is aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle, or -chalcogen-alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted;
Z 11 and Z 12 are independently alkyl, hydroxy, alkoxy, aryloxy, or Z 11 and Z 12 together form a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and
A 10 is 0, 1, or 2.
78 . The method of claims 67 , 68 , 69 , 70 , 71 , 72 , 73 , 75 , 76 or 77 wherein said protesome inhibitor is one of:
N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid,
N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid,
N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid,
N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid,
N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid,
N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid,
N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid,
N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, or
N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or
isosteres, pharmaceutically acceptable salts or boronate esters thereof.
79 . A method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a compound of claim 58 or 61 .
80 . A method for reducing the activity of NF-κB in a cell comprising contacting said cell with a compound of claim 58 or 61 .
81 . A method for reducing the rate of intracellular protein breakdown comprising contacting cells with a compound of claim 58 or 61 .
82 . A method for reducing the rate of degradation of p53 protein in a cell comprising administering to said cell a compound of claim 58 or 61 .
83 . A method for inhibiting cyclin degradation in a cell comprising contacting said cell with a compound of claim 58 or 61 .
84 . A method of preventing or treating an inflammatory condition in a patient in need thereof, said method comprising administering to said patient a compound of claim 58 or 61 .
85 . The method of claim 84 , wherein said patient has been diagnosed with, or is at risk of developing, a condition selected from the group consisting of tissue rejection, organ rejection, arthritis, an infection, dermatoses, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and an autoimmune disease.
86 . A method for inhibiting the growth of a cancer cell, comprising contacting said cell with a compound of claim 58 or 61 .
87 . A method for inhibiting antigen presentation in a cell comprising administering to said cell a compound of claim 58 or 61 .
88 . A method for inhibiting NF-κB dependent cell adhesion in an animal comprising administering to said animal a compound of claim 58 or 61 .
89 . A method for inhibiting HIV replication in an animal comprising administering to said animal a compound of claim 58 or 61 .Join the waitlist — get patent alerts
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